Cannabidiol/cannabidiolic acid-rich hemp (Cannabis sativa L.) extract attenuates cognitive impairments and glial activations in rats exposed to chronic stress

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“Ethnopharmacological relevance: Hemp (Cannabis sativa L.) is increasingly being recognized for its medicinal properties beside utilizing it for food, oil, and textile fibers. The high level of cannabidiol (CBD) content in hemp’s flowers shows promising neuroprotective properties without causing psychotomimetic or addictive effects. Recently, products containing CBD and its precursor, cannabidiolic acid (CBDA), have been used to treat stress-related cognitive impairment. However, the therapeutic potential of hemp extract remains inadequately explored.

Aim of the study: To investigate the effect of CBD/CBDA-rich hemp extract on learning and memory, neuroendocrine alterations, and hippocampal neuropathological changes in the chronic restraint stress model.

Materials and methods: Chronic restraint stress (CRS) was induced in male Wistar rats by immobilizing them in a restrainer for 6 hours per day for 21 consecutive days. CBD/CBDA-rich hemp extract (10 and 30 mg/kg, intraperitoneal injection) was administered daily, 1 hour before restraint. After the last day of CRS, behavioral tests for cognition were conducted using the Y-maze and object recognition tests. Serum corticosterone (CORT) levels were measured by ELISA. Histopathological changes, neuronal density, and the activation of microglia and astrocytes were visualized using cresyl violet and immunohistochemical staining.

Results: A high dose of CBD/CBDA-rich hemp extract effectively ameliorated CRS-induced cognitive impairment and reversed HPA axis hyperactivity in CRS rats by reducing CORT levels and adrenal gland weight. Additionally, CBD/CBDA-rich hemp extract protected CRS-induced damage to hippocampal neurons. Further analysis showed that CBD/CBDA-rich hemp extract reduced specific markers of microglial activation (ionized calcium-binding adaptor molecule-1, Iba-1) and astrocytic structural protein (glial fibrillary acidic protein, GFAP) in CRS rats.

Conclusion: CBD/CBDA-rich hemp extracts remarkably reversed the stress-induced behavioral perturbations and hippocampal damage, suggesting its ameliorative effect on stress response.”

https://pubmed.ncbi.nlm.nih.gov/39551282/

“Cannabidiol (CBD) and cannabidiolic acid (CBDA) is the major constituent in hemp (Cannabis sativa L.) extract”

“CBD/CBDA-rich hemp extract is effective in relieving the chronic stress-induced cognitive impairment.”

https://linkinghub.elsevier.com/retrieve/pii/S0378874124014120

Cannabis Use and Age-Related Changes in Cognitive Function From Early Adulthood to Late Midlife in 5162 Danish Men

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“Introduction: Cannabis is by far the most widely used and abused drug listed on the Drug Enforcement Administration’s Schedule I, which includes drugs with a high potential for abuse. There is evidence of short-term negative effects of cannabis use on cognition, but only a limited number of studies have explored the association between cannabis use and age-related cognitive decline. The aim of the present study was to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife.

Methods: The study population consisted of 5162 men who had participated in Danish follow-up studies on cognitive aging. These studies included scores on the military intelligence test Børge Prien’s Prøve from both the conscription assessment (mean age = 20 years; p1 and p99: 18 and 26 years) and from the follow-up (mean age = 64 years; p1 and p99: 55 and 72 years) as well as extensive data on lifestyle and health from the follow-up questionnaires. The association between cannabis use and age-related cognitive decline was investigated in linear regression models.

Results: Men with a history of cannabis use had less cognitive decline from early adulthood to late midlife compared to men without a history of cannabis use. Among cannabis users, neither age of initiation of cannabis use nor frequent use was significantly associated with a greater age-related cognitive decline.

Discussion and conclusions: In a sample of more than 5000 men followed for a mean of 44 years, we found no significant harmful effects of cannabis use on age-related cognitive decline.”

https://pubmed.ncbi.nlm.nih.gov/39508467/

“In the present study, we aimed to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife. This study contributes to the sparse knowledge on this subject and aligns with most existing studies, suggesting no association between cannabis use and greater cognitive decline. More specifically, in the present study, cannabis users experienced slightly less cognitive decline compared to nonusers, and the association remained significant when controlling for potential confounders. Among cannabis users, no significant association was found with cognitive decline for either age of initiation of cannabis use or frequent cannabis use. Further studies are needed to investigate whether these findings reflect that there are no adverse effects on cognitive decline or that the effects of cannabis are temporary and disappear after a prolonged period of time.”

https://onlinelibrary.wiley.com/doi/10.1002/brb3.70136

Cannabinoid for alcohol use disorder

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“Several pieces of evidence have implicated the endocannabinoid system on dopaminergic mesolimbic brain reward, as well as the potential role of cannabinoid receptors CB1 and CB2 on modulation of reinforced properties of drug abuse and consequently to the treatment of substance use disorder, including alcoholism.

Moreover, growing evidence has been proposed that cannabis or cannabinoid compounds may be helpful to treat alcohol use disorder (AUD).

Cannabis is prevalent among individuals who also consume alcohol. While some authors reported that cannabis may be a promising candidate as a substitute medication for AUD, some studies have demonstrated that concomitant use of alcohol and cannabis may increase the risk of adverse outcomes.

Considering that advances in the legalization and decriminalization movements regarding cannabis have led to increased availability worldwide, the current chapter aims to provide evidence on the benefits and risks of combining alcohol and cannabis, as well as the potential therapeutic use of cannabinoid compounds in treating AUD.”

https://pubmed.ncbi.nlm.nih.gov/39523058/

“Growing studies have indicated that medicinal cannabis could be reasoned as a substitute therapy for alcohol, especially among individuals who are trying to reduce drinking behavior. Based on these premises, medicinal cannabis might be safer and also produce less social harms, for this reason some studies have been pointed as a good candidate for substitute medication for alcohol.”

https://www.sciencedirect.com/science/article/abs/pii/S0074774224001089?via%3Dihub

UK medical cannabis registry: A clinical outcome analysis of medical cannabis therapy in chronic pain patients with and without co-morbid sleep impairment

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“Introduction: Chronic pain (CP) affects 35.0%-51.3% of the UK population, with 67%-88% reporting sleep disturbances. Cannabis-based medicinal products (CBMPs) have shown therapeutic potential in managing CP. Evidence suggests poor sleep worsens pain perception; therefore, this study aimed to assess patient-reported outcome measures (PROMs) following CBMP treatment in CP patients with and without co-morbid sleep impairment.

Methods: A prospective cohort study of CP patients from the UK Medical Cannabis Registry was conducted. Participants were separated by baseline single-item sleep quality scale (SQS) score into sleep impaired (SQS ≤3) and unimpaired (SQS ≥4) cohorts. The primary outcome assessed changes in PROMs from baseline to 1-, 3-, 6-, and 12-months. Participants completed the following: SQS, General Anxiety Disorder-7, EQ-5D-5L, Brief Pain Inventory (BPI), and Short-Form McGill Pain Questionnaire-2. Significance was defined as p < 0.050.

Results: 1139 participants met the inclusion criteria (sleep impaired: n = 517, 45.4%; sleep unimpaired: n = 622, 54.61%). The sleep impaired cohort showed improvements in all PROMs at each follow-up (p < 0.010). The sleep unimpaired cohort showed similar results (p < 0.050), except in SQS and ED-5Q-5L: self-care and anxiety/depression scores (p > 0.050). However, the sleep impaired cohort observed greater improvements in BPI pain severity (p < 0.050) and SQS (p < 0.001) than the sleep unimpaired cohort at all follow-ups. 2817 adverse events were self-reported between both cohorts (p = 0.197).

Discussion: These findings align with literature that shows associated improvements in pain outcomes following CBMP administration. Sleep impaired individuals were more likely to experience greater pain severity improvements. However, this was not confirmed on multivariate logistic regression analysis and instead may be confounded by baseline pain severity.

Conclusion: Whilst these results show promise for the effects of CBMPs on CP, they must be examined within the limitations of the study design. These findings provide further evidence to support the design of subsequent randomized controlled trials to verify causality between CBMPs and pain outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39545361/

“The results of this observational cohort study suggest an association between CBMP treatment and improvement in pain-specific and HRQoL PROMs in CP patients with and without co-morbid sleep impairment. Notably, those with co-morbid sleep impairment were associated with greater improvements in BPI pain severity, SQS, and PGIC than those without. However, this finding was not confirmed on multivariate analysis. Reported sleep quality did improve across the cohort from baseline, and when present was also associated with improvements in pain severity, suggesting that the effects of CBMPs on sleep may provide additional benefits for individuals with chronic pain beyond affecting the transmission of nociceptive signals. At the onset of treatment, however, other variables may be better prognostic markers for response to CBMP treatment, such as severe pain or anxiety at baseline. With respect to clinical significance, 44.10% report an improvement in the sleep impaired cohort at 1-months, declining to 24.56% at 12-months. Despite being limited by its observational design, the present study can be used to inform future RCTs, in addition to current clinical practice.”

https://onlinelibrary.wiley.com/doi/10.1111/papr.13438

Therapeutic potential of minor cannabinoids in psychiatric disorders: A systematic review

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“Interest in cannabinoids’ therapeutic potential in mental health is growing, supported by evidence of the involvement of the endocannabinoid system in psychiatric disorders such as anxiety, depression, and addiction.

While the major cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have been more extensively researched, approximately 120 minor cannabinoids from the cannabis plant have been identified. Although some displayed promising pharmacological profiles, research on their application for psychiatric disorders is fragmented.

This systematic review evaluates, for the first time, both preclinical and clinical studies exploring minor cannabinoids’ therapeutic potential in psychiatric disorders. 22 preclinical studies and one clinical study were included, investigating various minor cannabinoids in substance use disorders, anxiety disorders, depressive disorders, trauma and stressor-related disorders, psychotic disorders, neurodevelopmental disorders, and eating disorders. Despite the heterogeneous results and the moderate to high risk of bias in several articles, certain compounds demonstrate promise for further investigation.

Δ8-tetrahydrocannabidivarin (Δ8-THCV) exhibited potential for nicotine addiction; Δ9-tetrahydrocannabidivarin (Δ9-THCV) for psychotic-like symptoms; cannabidiolic acid methyl ester (CBDA-ME) alleviated anxiety and depression-like symptoms, and cannabidivarin (CBDV) autism spectrum disorder-like symptoms.”

https://pubmed.ncbi.nlm.nih.gov/39541799/

https://www.sciencedirect.com/science/article/pii/S0924977X24007508?via%3Dihub

Secondary metabolite profiles and anti-SARS-CoV-2 activity of ethanolic extracts from nine genotypes of Cannabis sativa L

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“This study deals with the comprehensive phytochemical composition and antiviral activity against SARS-CoV-2 of acidic (non-decarboxylated) and neutral (decarboxylated) ethanolic extracts from seven high-cannabidiol (CBD) and two high-Δ9-tetrahydrocannabinol (Δ9-THC) Cannabis sativa L. genotypes.

Their secondary metabolite profiles, phytocannabinoid, terpenoid, and phenolic, were determined by LC-UV, GC-MS, and LC-MS/MS analyses, respectively. All three secondary metabolite profiles, cannabinoid, terpenoid, and phenolic, varied significantly among cannabinoid extracts of different genotypes.

The dose-response analyses of their antiviral activity against SARS-CoV-2 showed that only the single predominant phytocannabinoids (CBD or THC) of the neutral extracts exhibited antiviral activity (all IC50 < 10.0 μM). The correlation matrix between phytoconstituent levels and antiviral activity revealed that the phenolic acids, salicylic acid and its glucoside, chlorogenic acid, and ferulic acid, and two flavonoids, abietin, and luteolin, in different cannabinoid extracts from high-CBD genotypes are implicated in the genotype-distinct antagonistic effects on the predominant phytocannabinoid.

On the other hand, these analyses also suggested that the other phytocannabinoids and the flavonoid orientin can enrich the extract’s pharmacological profiles. Thus, further preclinical studies on cannabinoid extract formulations with adjusted non-phytocannabinoid compositions are warranted to develop supplementary antiviral treatments.”

https://pubmed.ncbi.nlm.nih.gov/39543317/

“Our studies showed that neutral extracts of different C. sativa genotypes have antiviral properties against SARS-CoV-2 though further preclinical studies on formulations of these extracts are needed to enhance their antiviral potential. One direction of these studies might be to obtain the extract formulations with modified non-phytocannabinoid compositions and asses their antiviral potential.”

https://onlinelibrary.wiley.com/doi/10.1002/ardp.202400607

Blood pressure and hypertension in older adults with a history of regular cannabis use: findings from the Multi-Ethnic Study of Atherosclerosis

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“Background: Observational evidence investigating associations between cannabis use and blood pressure and hypertension is inconsistent.

Methods: Cross-sectional data from 3,255 participants at Exam 6 (2016-2018) of the Multi-Ethnic Study of Atherosclerosis (MESA) were analyzed, including self-reported cannabis smoking patterns, standardized measures of systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP; BP collectively), and hypertension. ANCOVA and multivariable relative risk regression models were used to calculate adjusted means for BP and adjusted prevalence ratios (PRs) for prevalent hypertension.

Results: In fully adjusted ANCOVA models, a history of regular cannabis smoking, when compared to no history, was not significantly associated with increased SBP [mean difference: 0.1 mmHg (95% CI: -1.6-1.9)], DBP [mean difference: 0.5 mmHg (95% CI: -0.3-1.4)], PP [mean difference: -0.5 mmHg (95% CI: -1.8-0.9)], or prevalent hypertension [PR: 1.01 (95% CI: 0.93-1.10)]. Furthermore, no associations were observed for either the duration or recency (in the past month) of cannabis smoking or number of joint/pipe years. Models exploring potential interactions between a history of regular cannabis smoking and age, sex, race/ethnicity, and cigarette smoking status were not significant for either BP or hypertension.

Conclusions: In a cohort of racially and ethnically diverse older adults with a high prevalence of hypertension, no evidence of increased risk due to regular cannabis smoking was found for either blood pressure or hypertension.”

https://pubmed.ncbi.nlm.nih.gov/39539498/

“In a cohort of racially and ethnically diverse older adults with a high prevalence of hypertension, no evidence of increased risk due to regular cannabis smoking was found for either blood pressure or hypertension.”

https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2024.1432923/full

A sleepy cannabis constituent: cannabinol and its active metabolite influence sleep architecture in rats

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“Medicinal cannabis is being used worldwide and there is increasing use of novel cannabis products in the community. Cannabis contains the major cannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), but also an array of minor cannabinoids that have undergone much less pharmacological characterization.

Cannabinol (CBN) is a minor cannabinoid used in the community in “isolate’ products and is claimed to have pro-sleep effects comparable to conventional sleep medications. However, no study has yet examined whether it impacts sleep architecture using objective sleep measures. The effects of CBN on sleep in rats using polysomnography were therefore examined.

CBN increased total sleep time, although there was evidence of biphasic effects with initial sleep suppression before a dramatic increase in sleep. CBN increased both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. The magnitude of the effect of CBN on NREM was comparable to the sleep aid zolpidem, although, unlike CBN, zolpidem did not influence REM sleep.

Following CBN dosing, 11-hydroxy-CBN, a primary metabolite of CBN surprisingly attained equivalently high brain concentrations to CBN. 11-hydroxy-CBN was active at cannabinoid CB1 receptors with comparable potency and efficacy to Δ9-THC, however, CBN had much lower activity. We then discovered that the metabolite 11-hydroxy-CBN also influenced sleep architecture, albeit with some subtle differences from CBN itself.

This study shows CBN affects sleep using objective sleep measures and suggests an active metabolite may contribute to its hypnotic action.”

https://pubmed.ncbi.nlm.nih.gov/39528623/

“In conclusion, for close to 50 years there has been the suggestion that the minor plant cannabinoid CBN increases sleep without any robust scientific evidence based on objective sleep measures. This study provides the first objective evidence that CBN influences sleep architecture and that its hypnotic effects may involve an active metabolite.”

https://www.nature.com/articles/s41386-024-02018-7

“Study confirms what cannabis users have long known. Study may lead to new treatment for sleep disorders like insomnia, researchers say”

https://www.independent.co.uk/news/science/cannabis-use-sleep-link-compound-b2646151.html

CB1 Receptors In NG2 CELLS MEDIATE CANNABINOID-EVOKED FUNCTIONAL MYELIN REGENERATION

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“Defects in myelin homeostasis have been reported in many neuropathological conditions. Cannabinoid compounds have been shown to efficiently promote myelin regeneration in animal models of demyelination. However, it is still unknown whether this action relies mostly on a cell autonomous effect on oligodendroglial-lineage-NG2 cells.

By using conditional genetic mouse models, here we found that cannabinoid CB1 receptors located on NG2 cells are required for oligodendroglial differentiation and myelin regeneration after demyelination. Selective CB1 receptor gene depletion in NG2 cells following toxin-induced demyelination disrupted oligodendrocyte regeneration and functional remyelination and exacerbated axonal damage. These deficits were rescued by pharmacological blockade of the RhoA/ROCK/Cofilin pathway.

Conversely, tetrahydrocannabinol administration promoted oligodendrocyte regeneration and functional remyelination in wild-type but not Ng2-CB1-deficient mice.

Overall, this study identifies CB1 receptors as essential modulators of remyelination and support the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/39528076/

“Cannabinoids have been shown to modulate myelin development and regeneration in mice. Here, using OPC-specific reporter mouse lines in combination with models of toxin-induced demyelination, we found that CB1 receptors located on NG2 cells, by modulating RhoA/ROCK/cofilin and mTORC1 signaling in a coordinated manner, exert an essential function in controlling NG2 cell differentiation, OL regeneration, myelin regeneration and functional recovery following demyelination, thus supporting the therapeutic potential of cannabinoids for promoting remyelination in neurological disorders.”

https://www.sciencedirect.com/science/article/abs/pii/S0301008224001199?via%3Dihub

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer’s Disease by In Silico, In Vitro, and In Vivo Studies

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“Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production.

A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out.

CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands.

The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay.

Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs.”

https://pubmed.ncbi.nlm.nih.gov/39510547/

“In summary, we have shown that both CBDA and CBGA are endowed with a multitarget ligand profile, acting not only as dual PPARα/γ agonists but also as inhibitors of both cholinesterase and BACE-1 enzymes, and molecular targets are currently used in the AD therapy to show down the cognitive impairment associated to the disease, thus providing a rationale for their in vivo activity.”

https://onlinelibrary.wiley.com/doi/10.1002/ptr.8369